Our goal is to determine the clinical, cognitive, imaging, genetic and biochemical biomarker characteristics of the early (pre-dementia) stages of Alzheimer's disease (AD). The project builds on the NIA-funded AD Neuroimaging Initiative (ADNI1) and serves as a bridge to the planned renewal of ADNI (ADNI2). Our model posits: AD begins with A2 deposition in cortex, leading to synaptic dysfunction, neurodegeneration, and cognitive/ functional decline. The earliest detectable changes are decreased CSF A2 and increased PET amyloid tracer retention. Subsequently, neurodegeneration is detected by increased CSF tau species, synaptic dysfunction by FDG-PET retention and neuron loss indicated by hippocampal atrophy (measured with MRI). These changes ultimately lead to memory loss then general cognitive decline and dementia. This sequence is influenced by factors including age, APOE genotype, cerebrovascular disease, and other pathologies. We propose three overarching themes with specific operational hypotheses using data from ADNI1 and GO. 1) Reductions of CSF A2 and increased amyloid PET intensity are present in some asymptomatic individuals, indicating the early stage of AD neurobiology. 2) Subsequently, CSF tau increases accompanied by reduced brain glucose metabolism (assessed by FDG-PET) and an increased rate of medial temporal lobe atrophy, and 3) after the aforementioned events, memory impairment appears, eventually progressing to dementia. Our specific aims are: 1: Define and enroll subjects with early amnestic MCI (EMCI) to fill the gap between controls and "late MCI (LMCI)" subjects currently enrolled in ADNI. EMCI subjects will meet clinical criteria for amnestic MCI, performing between 0.0 and 1.5 SD below the mean of elderly controls on delayed paragraph recall performance. Long term follow-up of the subjects will be accomplished by the renewal of ADNI (ADNI2). 2: Perform F18 amyloid imaging on the normal and LMCI subjects from ADNI1 and the newly enrolled EMCI subjects from GO. This will establish a national network for F18 amyloid imaging, and test hypotheses concerning the prevalence and severity of brain amyloid in this group relating amyloid deposition to current and previous changes in clinical state, MRI, FDG PET and CSF and plasma biomarkers from ADNI1. 3: Continue longitudinal studies of LMCI and cognitively normals of ADNI1 for an additional year. 4: Analyze all existing and new clinical biochemical neuroimaging and biomarker data from ADNI1 and GO. ADNI1 was funded and only provided to analyze the first year's data, but subjects have now been followed for 3-4 years with more follow-up in GO. Thus a large longitudinal data set will be analyzed. Taken together, the overall impact of this GO grant will be: 1) increased knowledge concerning the sequence of events leading to AD dementia;2) development of improved clinical and biomarker methods for early detection of AD;3) improved imaging/biomarkers for monitoring progression of AD, facilitating drug discovery. PUBLIC HEALTH RELEVANCE: The goal of this project is to determine the relationships among the clinical, cognitive, imaging, genetic and biochemical biomarker characteristics of the early (pre-dementia) stages of Alzheimer's disease (AD). The project builds on the NIA- currently funded AD Neuroimaging Initiative (ADNI1, a collaboration between academia and industry to study biomarkers of AD) and serves as a bridge to the renewal of ADNI (termed ADNI2). The overall impact of this project will be: 1) increased knowledge concerning the sequence of events leading to AD dementia;2) development of improved clinical and biomarker methods for early detection of AD;and 3) improved imaging and chemical biomarker methods for monitoring progression of AD, facilitating clinical trials of treatments to slow disease progression, and ultimately contributing to the prevention of AD dementia.